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FRI0370 Efficacy and safety of lesinurad (RDEA594), a novel URAT1 inhibitor, in combination with allopurinol in allopurinol-refractory gout patients: Results from a randomized, blinded, placebo-controlled, phase 2b extension study
  1. F. Perez-Ruiz1,
  2. J. Sundy2,
  3. E. Krishnan3,
  4. V. Hingorani4,
  5. J. Welp4,
  6. T. Rodgers4,
  7. K. Manhard4,
  8. M. Cravets4,
  9. D. Hagerty4,
  10. B. Quart4
  11. on behalf of Ardea Biosciences, Inc.
  1. 1Hospital de Cruces, Baracaldo, Vizcaya, Spain
  2. 2Duke University Medical Center, Durham, NC
  3. 3Stanford University School of Medicine, Stanford, CA
  4. 4Ardea Biosciences, Inc, San Diego, CA, United States

Abstract

Background Lesinurad (LESUR) is an oral investigational URAT1 inhibitor for the treatment of gout. A Phase 2B study in 208 gout patients with an inadequate response to allopurinol (ALLO) (200-600 mg/day for ≥6 weeks) demonstrated that the combination of LESUR+ALLO resulted in superior reductions in sUA with 79%, 74%, and 63% of patients achieving sUA <6 mg/dL after 28 days of dosing with 600 mg, 400 mg and 200 mg LESUR, respectively, compared to 25% with placebo (PBO)+ALLO (p<0.0001 for all comparisons). Subjects completing the Phase 2B study could enter a 44-week, blinded, PBO-controlled extension, the results of which are presented here.

Objectives To assess the ongoing efficacy and safety of LESUR in combination with ALLO vs. PBO+ALLO in patients with an inadequate response to standard doses of ALLO.

Methods Subjects completing the double-blind 28-day main study were washed out of LESUR or PBO before entering the blinded extension period, but remained on a stable dose of ALLO. Subjects then restarted their original blinded treatment of LESUR or PBO. All LESUR-treated subjects started on the 200 mg dose and were to have the dose titrated stepwise to 400 or 600 mg if the sUA was not <5 mg/dL. After dose escalation of LESUR or PBO, ALLO dose could be escalated.

Results 126 subjects enrolled into the blinded extension study (78 LESUR and 48 PBO); 91 subjects completed 44 weeks at time of this analysis. 78% of LESUR treated subjects maintained sUA <6 mg/dL at 44 weeks, compared to 56% of PBO subjects (LOCF analysis); 59% of subjects receiving LESUR also achieved sUA<5 mg/dL compared to 25% of PBO subjects. ALLO doses were increased in the majority of PBO subjects. 29 subjects (13 PBO/16 LESUR) withdrew from the study for any reason before Week 44. Overall rates of adverse events (AEs) were low and similar between the treatment groups. 4 subjects reported serious AEs (angina pectoris, cerebral artery embolism, tendon rupture, bursitis infective) considered not related to treatment. Transient serum creatinine (sCr) elevations were observed in both groups; on LESUR these generally occurred early or after dose escalations and usually resolved to within the normal range while on LESUR. 4 subjects discontinued due to increased sCr; 1 receiving PBO and 3 on LESUR. Monthly gout flare rates for subjects remaining on the 200 mg dose were generally lower for the LESUR group compared to PBO during Months 7-12.

Conclusions In patients who do not respond adequately to ALLO, the addition of LESUR produced consistent, sustained reductions in sUA levels, with the majority of subjects achieving sUA levels of <6 mg/dL and <5 mg/dL. Despite dose increases of ALLO in the majority of PBO subjects, combination therapy was superior. LESUR was well-tolerated with a similar rate of AEs to placebo. The premature discontinuation rate on PBO was higher than on LESUR. LESUR is a promising investigational drug for the treatment of hyperuricemia in gout patients.

Disclosure of Interest F. Perez-Ruiz Grant/Research support from: Asociaciόn de Reumatόlogos del Hospital de Cruces y Ministerio de Sanidad, Gobierno de España, Consultant for: Ardea Biosciences, Menarini Pharma, Novartis, Savient, Speakers Bureau: Menarini Pharma, Novartis, J. Sundy Grant/Research support from: Ardea Biosciences, Nuon Therapeutics, Pharmos, Regeneron, Celgene, Savient, Abbot, Jansen, Consultant for: Ardea Biosciences, Nuon Therapeutics, Pharmos, Novartis, Savient, Roche, E. Krishnan Grant/Research support from: Takeda, Consultant for: Takeda, V. Hingorani Consultant for: Ardea Biosciences, J. Welp Employee of: Ardea Biosciences, T. Rodgers Employee of: Ardea Biosciences, K. Manhard Employee of: Ardea Biosciences, M. Cravets Employee of: Ardea Biosciences, D. Hagerty Employee of: Ardea Biosciences, B. Quart Employee of: Ardea Biosciences

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